Triazole scaffolds emerge as versatile multitarget ligands for Alzheimer's disease therapy

The progression of Alzheimer's disease (AD) is primarily characterized by the extracellular deposition of amyloid-β (Aβ) peptide plaques and intracellular accumulation of hyperphosphorylated tau (p-tau) protein as neurofibrillary tangles (NFTs). Despite significant neuroscience advancements, developing effective therapeutic agents for AD remains challenging due to its complex, multifactorial pathology. Current standard-of-care often addresses only symptomatic relief or single targets, which falls short of halting disease progression. This highlights a critical need for molecules capable of modulating multiple targets involved in the disease cascade, offering a more comprehensive therapeutic strategy.

This comprehensive review systematically explored the structure-activity relationships, multitarget strategies, and therapeutic mechanisms of triazole scaffolds in Alzheimer's disease. Researchers performed a thorough literature search across PubMed, Scopus, Web of Science, and Google Scholar databases, covering publications from 2000 to 2026. The methodology involved critically analyzing the evolution of triazole-based therapeutics, from early single-target cholinesterase inhibitors to contemporary multitarget-directed ligands. The review focused on evaluating how the structural versatility of 1,2,3- and 1,2,4-triazole cores facilitates interactions with key AD pathological hallmarks.

Triazole scaffolds consistently demonstrate potent inhibitory activity against a diverse array of targets implicated in Alzheimer's disease progression. The review highlights their efficacy against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are crucial for neurotransmission. Beyond cholinergic modulation, triazoles also exhibit significant activity in mitigating amyloid beta (Aβ) accumulation and tau aggregation, two central pathological hallmarks. Furthermore, these versatile molecules have shown promise in addressing associated pathologies such as neuroinflammation and oxidative stress, both of which contribute to neuronal damage and cognitive decline in AD. The analysis underscores a clear evolution: > The 1,2,3-triazole scaffold, in particular, is frequently cited as a preferred choice for designing multifunctional hybrid molecules, enabling a single compound to engage with multiple pathological pathways simultaneously, moving beyond the limitations of single-target drugs. This multitarget approach leverages the inherent structural flexibility of triazoles to interact with diverse biological targets, offering a more holistic therapeutic strategy.